Pharmaceutical solid preparations sometimes have sustained release, enteric, or bitterness-masking film coating with a view to reducing side effects of a drug comprising in them, reducing the administration frequency, improving the effect of the drug, suppressing a bitter taste, stabilizing the drug, or the like. Drug-containing spherical granules having a dosage form suited for film coating thereon are called spherical base granules.
As a production method of spherical base granules, a method of carrying out extrusion granulation using a drug and an excipient as raw materials and then spheronizing the resulting granule product (extrusion-spheronization method), a method of coating the surface of spherical core particles with a drug (layering method) (refer to, for example, Patent Document 1), and the like are known.
In the layering method, granules are produced by spraying a layering liquid comprising a drug, a binder, and the like to spherical core particles to coat them with a coating layer. Specific examples of it include a method of simultaneously supplying drug powders and an aqueous solution of a binder and coating spherical core particles with them; a method of supplying a suspension of drug particles and coating the spherical core particles therewith; and a method of supplying an aqueous solution of a drug and coating the spherical core particles therewith.
The layering method is suited as a method for producing spherical base granules to be film-coated, because spherical base granules having a high sphericity and a narrow particle size distribution can be obtained using spherical core particles having a high sphericity and a narrow particle size distribution.
However, when a drug that is contained in the layering liquid has low water solubility (hardly water-soluble drug), dispersion in an apparatus having a high shear force is necessary to obtain a uniform suspension. Therefore, when such a layering liquid is prepared, vigorous foaming occurs, and foam breaking is sometimes necessary. In addition, in a layering liquid having a practical drug concentration, the drug particles precipitate with the passage of time. The layering liquid therefore must be stirred/mixed constantly to keep the suspension uniform. Even if the layering liquid is stirred/mixed constantly, there is a risk of a tube or spray nozzle being clogged with precipitated/agglomerated particles during a transfer of the layering liquid from a tank to the spray nozzle. When the drug has a large particle size, the above risk increases further, which leads to deterioration in adhesion to spherical core particles, a reduction in a recovery ratio, and an increase in agglomeration ratio due to inhibition of smooth tumbling. A reduction in the size of the drug particles improves suspension stability of the layering liquid and a recovery ratio, but it needs an extra pulverization (or grinding) treatment step of the drug particles.
It is known to add various additives to the layering liquid for the purpose of preventing detachment of the coated drug, controlling a dissolution rate of the drug, or stabilizing the layering liquid (refer to, for example, Patent Documents 2, 3, and 4). These prior arts however fail to improve the suspensibility of a hardly water-soluble drug. Patent Documents 2 to 4 include no description on the use of both micronized microcrystalline cellulose and an emulsifier in combination
Patent Document 5 discloses a technology of coating spherical core particles with a hardly water-soluble drug, an emulsifier, and the like in accordance with the layering method, but the technology specifically disclosed herein is a layering method in which drug powders and an aqueous solution of a binder are supplied simultaneously to coat therewith the particles. Patent Document 5 includes no description on the improvement of suspensibility during addition of a hardly water-soluble drug to a layering liquid.    Patent Document 1: Japanese Patent Application Laid-Open No. 63-301816    Patent Document 2: Japanese Patent Application Laid-Open No. 9-165329    Patent Document 3: Japanese Patent Application Laid-Open No. 9-67247    Patent Document 4: Published Japanese translation of PCT international publication No. 2005-536527    Patent Document 5: International Publication No. 2005/044240